Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Biomarkers and Pediatric Environmental Health
Bertram Lubin and Rachel Lewis
Children's Hospital Oakland Research Institute, Oakland, California
Abstract
It is now possible to identify biochemical and/or cellular changes in
humans due to exposure to an environmental toxin. These changes are called
biomarkers and are currently used in research studies to identify individuals
exposed to specific toxic substances. Advances in the field of biomarker
technology may have important implications for the detection, prevention,
and treatment of certain diseases in children. This technology may enable
physicians to screen children who have no clinically detectable illness
for evidence of exposure to specific toxins. Such information could lead
to implementation of preventive measures and development of new therapeutic
strategies. However, several important issues, including potential adverse
consequences resulting from the widespread use of this technology, must
be considered prior to its utilization within a clinical setting. Leaders
of the pediatric and public health communities should recognize the paucity
of scientific data in the pediatric environmental health area, and new approaches
to this important aspect of child health should be developed. This article
will address several of the issues involved in pediatric environmental health
and consider questions that should be answered as the potential for technology
transfer becomes a reality. --Environ Health Perspect 103(Suppl 6):99-104
(1995)
Key words: pediatric environmental health, biomarkers, environmental
hazards, environmental toxins, genetic testing, preventative medicine, pediatric
screening, lead testing
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
This work was supported in part by grants HL 27059 and
HL 20985 from the National Institutes of Health.
Address correspondence to Dr. Bertram Lubin, Children's
Hospital Oakland Research Institute, 747 52nd Street, Oakland, CA 94609.
Telephone (510) 428-3502. Fax (510) 428-3608.
Introduction
A variety of technical advances have enabled scientists to identify specific
changes in humans at the molecular and cellular levels that are secondary
to exposure to a particular environmental toxin. Alterations in DNA, changes
in protein structure, metabolites in urine or blood, and other "footprints"
of toxic exposure can now be recognized and are being used as research tools
in molecular epidemiology to identify and track toxic exposures. These molecular
or biochemical changes are called biomarkers. As technical advances in the
field of molecular genetics are made, it may become possible to detect biomarkers
at the DNA level that predict susceptibility to environmental toxins.
The use of these biomarkers in a clinical setting could facilitate the
diagnosis of conditions in children that occur as a result of exposure to
specific toxic substances. Application of this technology should enable
the physician to include specific environmental toxic exposures within the
differential diagnosis of childhood illnesses such as failure to thrive,
chronic dermatologic conditions, respiratory complaints, altered susceptibility
to infection, and perhaps even leukemia. The identification of a specific
biomarker should help to confirm that a child has been exposed to a particular
toxin and may provide a tool to monitor either the effects of the toxin
or the effects of therapy. Biomarkers may have especially useful applications
for regular screening of children living in environmentally hazardous areas
(1).
In this article we will discuss several environmental health issues in
which the distinction between child and adult is crucial. We will also discuss
questions that must be addressed prior to utilization of biomarker technology
within a pediatric clinical setting. We will emphasize the need for research
and education in the area of pediatric environmental health and will present
the concept of a comprehensive pediatric environmental health program as
a model for pursuing these goals.
The Child Is Not a Small Adult!
Pediatrics is a distinct field of medicine. It is based upon the recognition
that the child is not a small adult. Indeed, the child has unique metabolic
and physiologic pathways that are distinct from those described in adults.
Many of these differences are the result of developmental changes that are
initiated during fetal life and continue through adolescence. Some of these
differences between children and adults are:
- different metabolic pathways
- increased respiratory rate
- rapid lung growth
- long life expectancy (development of latent disease)
- high rates of activity
- diet
- natural curiosity
- more time spent near þoor level, and
- pica behavior.
The clinical manifestations of diseases in children, even when they are
due to similar agents and affect similar organ systems, are often quite
different from those in adults.
Unfortunately, the differences between children and adults have not received
adequate attention in the field of environmental health. This point was
repeatedly emphasized throughout the recent conference on Preventing Child
Exposures to Environmental Hazards: Research and Policy Issues (Washington,
DC, 18-19 March 1994). The lack of appreciation for the physiologic differences
between children and adults has resulted in the development of environmental
safety standards that continue to permit substantial risks to children.
Even when we consider toxins more likely to affect children than adults,
we find that environmental safety standards such as those for pesticides
do not always take into account differences in the size, intake, respiratory,
or metabolic characteristics of a child (2).
There appear to be many reasons why the child is likely to be more susceptible
than the adult to the effects of an environmental toxin. Among these, the
most important is the child's inability to recognize certain toxins and
to avoid certain exposures. This is especially true for infants and toddlers.
In addition, differences in metabolic pathways required for activation or
degradation of toxic compounds, relationships between dose and surface area
or mass, water and/or caloric intake relative to surface area, and ability
to excrete hazardous substances through renal or hepato-biliary pathways
contribute to the child's inability to tolerate doses of toxins that might
be less harmful to an adult.
It is likely that the fetus and infant are even more susceptible to the
damaging effects of environmental toxins than the child. For example, a
number of metabolic pathways required to detoxify chemicals may be lacking
in the fetus and poorly developed in the infant. Since environmental toxins
can cross the placenta, certain chemicals may concentrate in the fetus and
cause permanent damage during critical phases of development. The effects
of environmental toxic exposure during fetal development are likely to be
greater than those observed in adults due to the rapid cellular changes
accompanying fetal growth. The brain, with its high lipid content, provides
an ideal milieu for hydrophobic toxic solvents, and effects on central nervous
system tissues are likely to be amplified during this period of rapid brain
growth. The child's pulmonary physiology, with rapid respiration rates and
lung growth, also lends itself to complications arising from airborne toxins
(3-8).
Advances in the field of biomarker technology could have wide application
in children's health care. As this technology is developed, it will be important
to identify appropriate biomarkers by identifying the types of exposure
that are most common in children. It is of crucial importance to recognize
that many biomarkers used to detect changes in adults may not be applicable
to children. From the technical standpoint, for biomarkers to be used in
a clinical setting, methods to collect samples will need to be appropriate
for the child's age as well as for intrauterine analysis in the event of
a toxic exposure during pregnancy.
Biomarkers as a Research Tool
Biomarkers have been used in a number of research programs to identify
and quantify toxins and to determine the effects of a specific toxin on
laboratory animals that have been intentionally exposed to specific doses
of the toxic substance (9). When used successfully, these biomarkers
have enabled investigators to identify effects of the toxin at the molecular
level and to identify animals affected by the exposure. However, the relationship
between the biomarker and the clinical consequences of the exposure frequently
are difficult to establish. In some cases, the animals have developed diseases
similar to those observed in humans at comparable exposure levels. In most
of the animal models studied, though the biomarker serves to identify an
affected animal, it cannot be used to predict the physiologic as well as
the long-term effects of the exposure.
In addition to their applications in experimental systems, biomarkers
have been used in clinical and epidemiologic research to document toxic
exposures and to investigate genetic susceptibility to environmental toxins
in humans. Though there have been a number of studies of adults exposed
to environmental toxins, limited environmental research has been performed
using biomarkers to identify affected children. Since biomarkers can be
found using small blood samples, urine, or, in some cases, skin, there is
no reason that this technology could not be used to evaluate children who
have potentially been exposed to an environmental hazard. However, except
in cases such as lead, radon, asbestos, and some pesticide exposures, there
have been very few attempts to develop new biomarker techniques to identify
toxic exposures in children (10). One of the objectives of the authors
of this article is to encourage scientists working in this field to consider
the needs of the child and to develop technology so that appropriate biomarkers
can be used widely in a pediatric setting. Advantages of biomarker technology
include early detection of toxic exposure, tracking of disease treatment,
preventive screening for toxic exposure in high-risk areas, screening during
pregnancy, and inclusion of toxic exposure in differential diagnosis.
Molecular Medicine and Pediatric Environmental Health
In several areas of medicine, the application of molecular biology techniques
to clinical problems has dramatically improved the ability to diagnose and
treat diseases in children. Within the next decade, in addition to improved
molecular methods for DNA diagnosis, basic science advances are likely to
result in gene therapy for a number of genetic conditions affecting children.
In this section, we will brieþy discuss the impact that this molecular
technology might have on the transfer of biomarker technology into a clinical
setting.
The list of diseases that can be detected by gene analysis has increased
dramatically in the last decade and is likely to continue to increase as
a consequence of current efforts to map the human genome. In the pediatric
field, this technology has made possible the identification of both genetic
traits and genetic diseases. Newborn screening programs have incorporated
many of these advances when the genetic information can be used to benefit
the child, and programs like the state-mandated newborn screening for hemoglobinopathies
are employed on a national scale to diagnose and treat children born with
diseases such as sickle cell anemia and thalassemia. It may soon be possible
to identify susceptibility to certain cancers and atherosclerosis in screening
programs. Further development of this technology ideally will lead us beyond
the identification of existing conditions to the point where we may begin
to identify genes that render a child susceptible to a disease or to damage
caused by an environmental toxin (11-15).
Intrauterine diagnosis is possible for a variety of genetic diseases
using molecular techniques. Although this has not been attempted to date,
it is possible that DNA alterations or other biomarkers consistent with
a specific environmental exposure can be identified in cells obtained from
amniotic þuid. This information could be used to predict consequences
in situations in which pregnant women have been exposed to environmental
toxins. The availability of such biomarkers could help the pediatrician
who is asked about the impact of a specific environmental toxin during pregnancy.
As researchers identify cancer susceptibility genes, genes that determine
the ability to catabolize environmental toxins, and genes that may be altered
as a consequence of parental exposure to environmental toxins, we will be
faced with decisions regarding the usefulness of this information and the
value of incorporating screening for these genes within existing screening
programs. For genetic diseases, screening procedures have been mandated
when therapies for the disorders are recognized. Will we have similar therapies
for environmental agents? Should we mandate screening for environmental
agents in the absence of effective therapies?
Similarly, once the capability to detect a biomarker in the fetus is
accomplished, many new issues will have to be addressed. Is there a therapy
that can be used to prevent toxicity? Can this be started in utero?
What will be the impact of the exposure after the child is born? Finally,
should a therapeutic abortion be considered? We have no information on this
extremely important area and careful research studies covering basic science,
social science, and community awareness are important to conduct simultaneously
with the development of improved biomarker technology. Since the basis of
pediatric medicine is prevention, one would hope that we could develop procedures
to avoid environmentally induced disease in susceptible populations and
that we could implement these procedures on a national level.
Although there are instances where the transfer of genetic technology
from the laboratory to the clinic has been relatively uncomplicated, such
as those in the field of hematology, in certain cases, especially where
susceptibility to disease is involved, several social, legal, and medical
issues arise. These include concerns regarding access to genetic information,
use of genetic information for purposes that might not directly benefit
individuals being tested, and availability of services for individuals found
to have a genetic trait or disease. It is likely that the transfer of biomarker
technology to the clinical setting will raise a number of similar questions
and that resolution of these matters will require careful analysis, planning,
and the development of new public policies.
Pediatric Environmental Health and the Legal Community
If one reviews the medical records in many large children's hospitals,
the paucity of information on potential environmental toxins rapidly becomes
evident. For example, when the medical records of children evaluated for
respiratory illness were reviewed, fewer than 10% of the records indicated
that questions were asked about exposure to passive smoke. Similarly, in
patients presenting with behavioral problems and developmental irregularities,
records seldom indicate tests for blood lead levels or other environmental
toxins, though the symptoms have been correlated with lead exposures in
children (16,17). This lack of attention to environmental issues
in pediatrics indicates a pervasive skepticism among health care providers
about the need for environmental health programs and illustrates the need
to implement education programs addressing important issues in pediatric
environmental health. To be most effective, these educational programs must
be incorporated in medical school curricula, residency training programs,
and postgraduate medical education programs.
In contrast to pediatricians, who for the most part are skeptical of
the impact of environmental toxins on children, members of the legal community
are often the first to consider that a child's illness may be secondary
to an environmental toxin. When this question is raised by a lawyer, a referral
to a physician who is knowledgeable in this area must be made. However,
very few physicians are either capable of -- or interested in--providing
such a consultation. Since physicians often question a lawyer's motivation
for a referral, only infrequently is an evaluation actually made. A lack
of willingness to cooperate with lawyers may increase the number of children
who continue to suffer from environmentally induced diseases; and even when
a consultation is given, a lack of expertise and experience with environmental
medicine may result in a poor evaluation. Using a biomarker to assist in
this evaluation would help the physician confirm that an exposure might
have caused the child's illness.
A program developed by pediatricians and members of the legal community
to work together to address this important issue of child health should
be considered as part of the larger goal of raising awareness of the environmental
health field. Pediatric leaders must also investigate the possibility of
collaborating with lawyers and working within the legal system so that preventive
environmental health measures are developed to specifically address pediatric
concerns.
Technology Transfer, Environmental Health, and Clinical
Pediatrics
Given the limited awareness of or sensitivity to environmental issues
within clinical pediatrics, it is not surprising that technology transfer
involving use of biomarkers in clinical pediatrics is quite limited. At
the present time, although a few epidemiologic studies have been conducted
on children living near toxic dump sites, application of biomarkers to detect
environmental toxic exposures in the clinical setting has been primarily
for lead poisoning and passive exposure to environmental tobacco smoke (ETS)
(18-20).
The accurate measurement of blood lead in children has provided physicians
the opportunity to identify, treat, and potentially eliminate this environmental
hazard for children. The toxic effects of elevated blood lead have been
clearly demonstrated, and, unlike for most environmental hazards, standards
for blood lead have been established for children (21,22). Screening
programs based upon blood lead measurements are widespread, and in some
areas they are mandated by law. The acceptance and implementation of lead
screening programs in specific communities where there is high risk of lead
exposure demonstrates that when significant environmental health problems
are identified, political pressure spearheaded by community organizations
can lead to the development of programs to limit toxicity.
Unfortunately, the measurement of blood lead poisoning requires a venous
blood sample, and contamination of the blood sample is frequent. New technology
should be developed to screen for lead poisoning using a biomarker that
can be detected on a blood sample obtained by a fingerstick method. This
technology would expand the possibility of community-based screening, as
samples could be collected in homes without the need for a phlebotomist
or the expense of a laboratory visit. Furthermore, such a biomarker could
be used to monitor cellular changes secondary to lead toxicity.
Cotinine, a metabolic product of nicotine, can be found in the urine
of children who have been exposed to environmental tobacco smoke (ETS).
Studies of newborn infants have demonstrated that cotinine can be found
in their urine when the mother has a history of smoking. In this context,
cotinine can also be considered a biomarker. Although there is considerable
evidence that ETS is toxic to children and can lead to serious medical complications
(23-25), most pediatricians are not familiar with this test and laboratories
to perform the cotinine analysis are not readily available. Thus children
with asthma or bronchiolitis rarely have cotinine measured in their urine
even though the correlation between ETS and these diseases in children is
well established. This gap in technology transfer may be due to a number
of factors; certain to be among them is the lack of awareness on the part
of physicians of the value of this biomarker as a sign of exposure to ETS.
Technology transfer would provide a means for expanding research and development
in the biomarker field and would open up possibilities for wider application
of biomarkers in prevention and treatment programs.
Potential Adverse Consequences of Biomarker Identification
If and when an epidemiologic approach utilizes biomarkers in a pediatric
population, it is important to recognize the medical, psychological, and
sociological consequences of such studies. More than any other field of
medicine, use of biomarkers to identify a child's exposure or susceptibility
to toxins can have major consequences that must be considered carefully
prior to initiating a study.
Behavioral changes, abnormal growth patterns, susceptibility to infections,
skin rashes, and a host of other medical complications may be ascribed to
environmental toxins. However, these conditions may be completely unrelated
to the toxic agent. Unless we are able to specifically identify a causal
relationship between the biomarker and a disease, and have a therapy to
prevent disease onset or specifically treat manifest disease, we must proceed
cautiously with the application of biomarkers. Furthermore, as we develop
advanced technology that can be used to study environmental toxic exposures
in children, we must also consider research plans to determine the impact
of this information on the child and family. For example, once a parent
hears that a child has a biomarker that indicates exposure to an environmental
toxin, the family may perceive the child in a different light--as disabled,
frail, or damaged--whether or not the relationship between the biomarker
and disease process has been firmly established. The long-term effects on
a child's self-esteem could far outweigh the benefits of assessing the medical
risk in the first place.
As we improve our molecular capabilities for identification of genes
responsible for disease, we will have to develop guidelines on how to use
this information. What do we say to the parent who has a susceptible child?
Will we be providing information that will benefit the child and the family?
How we will protect this child from environmental toxins? Will the child
be able to obtain health insurance or employment as an adult? Will biomarkers
serve only to label the child or will they actually improve child health?
With justification, one could ask whether procedures to identify toxic exposures
help more than they create confusion. These issues, although not immediate,
must be considered as we advance the technology.
It will be equally important to consider research protocols to determine
the efficacy of biomarker tests. Although the validity of biomarkers has
been documented in cases in which adults have been exposed to certain environmental
toxins, similar applications in children's health are limited. Once this
technology becomes available, the issue of how to treat the child who has
a biomarker will surface. Will the marker disappear when the child is removed
from the toxic environment? Will the biomarker cause permanent alterations
in DNA and have long-term consequences such as malignant transformation?
Only sustained research tracking the transformation of given biomarkers
from detection through treatment will provide insight into the role that
biomarkers will play in medicine. Through research, some of the mystery
surrounding causal links between disease and marker will be dispelled as
long-term follow-up tracks the biomarker and correlates it with the clinical
picture. Answering questions such as these will play a significant role
in shaping the public policy that will arise from biomarker technology in
the clinical setting.
Recommendations
Physician Education
Other than pediatric programs to assess lead poisoning, there are no
recognized centers where children can be evaluated for medical conditions
resulting from exposure to environmental hazards. Most pediatricians have
no awareness of what should be considered in the evaluation of a child who
may have been exposed to an environmental toxin. The widespread skepticism
of environmental health among pediatricians will have an impact upon the
acceptance and use of biomarkers or molecular techniques to identify effects
of environmental toxins. A major educational effort, endorsed by the American
Academy of Pediatrics, will be required to change this pattern of thinking.
Educational programs addressing pediatric environmental health must be developed
for medical school curricula, pediatric residency programs, and perhaps
pediatric fellowships. Education programs in the community should be developed
simultaneously to inform community members about issues affecting their
children and to help them work toward a plan to improve the environment.
Such outreach is consistent with current political trends and should assist
in the development of laws to protect children against environmental hazards.
Collaboration between Pediatricians and the Legal Community
The authors would like to recommend further that pediatricians and lawyers
work together to identify environmental toxins and their effects on children.
With appropriate legal resources, policies and laws can be implemented to
help prevent exposures. The confidentiality of biomarker-related information
is particularly important to protect and studies to examine the efficacy
of these procedures should be conducted. Questions such as whether schools,
insurance agencies, or potential employers will use the information must
be considered to protect the rights of the child and family. Since we do
not yet know the long-term medical significance of any biomarker, how this
information is handled becomes extremely important.
The Creation of Comprehensive Pediatric Environmental Health Centers
Because the issues and technologies associated with pediatric environmental
health are so varied, coherent approaches to tackling the associated problems
are vitally important. The authors envision the creation of comprehensive
pediatric environmental health centers as a means for coordinating multifaceted
efforts to solve pediatric environmental health issues. Modeled after national
programs such as the Comprehensive Sickle Cell Centers, pediatric environmental
health centers would administer tests using biomarker technology, maintain
databases of current research and correlation between biomarkers and disease
development, provide counseling to affected children and parents, facilitate
basic and clinical research into environmental health concerns, and act
as resource centers for community members and pediatricians.
As a new health care plan is developed, the opportunity to address issues
in environmental health may become very difficult. The added costs of medical
and laboratory evaluations, and the outcome of such programs, are difficult
to determine at this point, since there are no comprehensive pediatric environmental
health centers upon which we can base cost/benefit decisions. Furthermore,
under managed care, the ability to obtain laboratory tests will be limited
unless clear-cut reasons for a particular test are established. Thus, it
will be important, as the ability to detect evidence of environmental toxins
in children is advanced, to incorporate such testing in a cost-effective
manner so that it will be available for children in need. This is particularly
important given the socioeconomic status of many children living under the
worst environmental conditions. It will be important to develop protocols
to evaluate the costs and benefits of comprehensive pediatric environmental
health centers and to determine if--and to what extent--they will eventually
reduce health care costs by improving child health. Recommendations for
a comprehensive pediatric environmental health center include the following:
- patient service projects
- public health research
- clinical and basic epidemiology research
- education programs
- public policy/legal analysts
- economists
- community involvement
- national database
- new pediatric environmental exposure standards.
New Epidemiological Studies with a Focus on Pediatric Issues
Reported studies to identify the effects of environmental toxins on children
are frequently conducted outside a pediatric medical center and primarily
involve epidemiologists and toxicologists. As with other research activities
funded by federal sources, topics are often chosen that have political impact
and that respond to priorities established by the scientific community.
Common problems in pediatrics that might be secondary to environmental toxins
are frequently not included, as they do not necessarily address well-recognized
national priorities. Furthermore, these studies may be more complicated
to perform and there is little preliminary data demonstrating causal relationships
between toxins and pediatric disease. Absence of this kind of information
does not mean that it is not important, and avenues to support these projects,
perhaps as a component of larger studies on environmental toxins, must be
considered.
Relationships between pediatric cancer and environmental toxins are among
the high priorities for research, and funding from federal agencies, although
not generous, has been provided. This area of research is very important,
as it represents one of the major complications secondary to an environmental
toxin. Although most studies on cancer are of scientific merit, performing
such research outside the mainstream of pediatrics does not lend itself
to subsequent incorporation of findings into a pediatric medical center.
An effort should be made to incorporate findings from such studies into
a national agenda on pediatric environmental health.
The most effective method for bringing advances in technology in pediatric
environmental health into a clinical pediatric setting is to encourage teamwork
between investigators and clinicians. Common objectives must be identified
and methods to evaluate technology must include input from basic and clinical
investigators. Such liaisons would fall under the aegis of the comprehensive
pediatric environmental health centers.
Conclusions
In conclusion, the authors recommend that national emphasis be placed
on developing comprehensive programs for pediatric evaluation for toxic
environmental exposures, physician education in detection and treatment
modalities, and basic research in the expanding field of biomarker technology.
In conjunction with development of technology and treatment, there must
be discussion and inquiry into the ethical and psychological issues that
inevitably will be associated with the application of this technology in
the clinical setting, and, most importantly, we must consider ways of preventing
misuse of diagnostic information.
Children, because of their rapid development and distinct physiologic
processes, are especially vulnerable to toxic exposures. Research that seeks
to correlate long-term disease profiles with exposure to environmental toxins
is an essential part of the broader effort to prevent and treat pediatric
illnesses.
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